Re-evaluation of the probabilities for productive rearrangements on the κ andλloci

V-J rearrangements at Ig light chain (IgL) genes occur in resting small pre-B cells. In the absence of cell division, the probability of productive κ and λ rearrangements is proportional to the output of κ+ B and λ+ B cells in bone marrow. The kinetics and probability of productive κ or λ rearrangements was assessed in three groups of mice carrying two (wild-type), one or no intact Ig gene, and the following conclusion are drawn,κ and λ rearrangements occur independently at different kinetics, and rearrangements are initiated at a time when κ rearrangements are stopping. The probability of productive κ and λ rearrangements per chromosome is calculated to be −60 and −20% respectively. Thus, a κ gene can attempt rearrangements up to three times per chromosome during B cell development. These findings explain that the observed ratio of κ+ B/λ+ B cell production in wild-type mice is 95/

Development of a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy

ABSTRACT: Pancreatectomy is an invasive surgery that is sometimes associated with complications. New-onset diabetes mellitus sometimes develops after partial pancreatectomy and severely affects the patient's quality of life. This study aimed to develop a preoperative prediction model of new-onset diabetes mellitus after partial pancreatectomy, which will help patients and surgeons to achieve more easily better common decisions on regarding whether to perform partial pancreatectomy. This retrospective cohort study analyzed medical records of patients who underwent partial pancreatectomy (total pancreatectomy excluded) from April 1, 2008, to February 28, 2016, which were available in the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The predictors were preoperative age, body mass index, hemoglobin A1c level, blood glucose level, and indication for partial pancreatectomy. The outcome was the development of new-onset diabetes mellitus at 1 to 12 months after partial pancreatectomy. We used a logistic regression model and calculated the scores of each predictor. To determine test performance, we assessed discrimination ability using the receiver operating characteristic curve and calibration with a calibration plot and the Hosmer-Lemeshow test. We also performed internal validation using the bootstrap method. Of 681 patients, 125 (18.4%) had new-onset diabetes mellitus after partial pancreatectomy. The developed prediction model had a possible range of 0 to 46 points. The median score was 13, and the interquartile range was 9 to 22. The C-statistics of the receiver operating characteristic curve on the score to predict the outcome was .70 (95% confidence interval [CI], .65-.75). Regarding the test performance, the Hosmer-Lemeshow test was not significant (P = .17), and calibration was good. In the bootstrapped cohorts, the C-statistics was .69 (95% CI, .62-.76). We developed a preoperative prediction model for new-onset diabetes mellitus after partial pancreatectomy. This would provide important information for surgeons and patients when deciding whether to perform partial pancreatectomy

Cohort profile: Alliance for Quality Assessment in Healthcare-Dialysis (AQuAH-D) prospective cohort study of patients on haemodialysis in Japan

PURPOSE: The global burden of kidney failure is increasing, but the treatment of kidney failure varies widely between patients, between dialysis facilities and over time. The Alliance for Quality Assessment in Healthcare-Dialysis (AQuAH-D) aims to conduct efficient and timely cohort studies on associations between those variations and clinical and patient-reported outcomes. PARTICIPANTS: Included are outpatients aged 20 years old or older who are undergoing haemodialysis and have consented to participate. A total of 2895 patients were enrolled from 25 facilities in Japan between August 2018 and July 2020 and are to be followed until 31 December 2026. Chart review and annual questionnaires are used to collect data on patient characteristics and on outcomes including quality of life. Data on medications, haemodialysis prescriptions and blood tests are obtained from existing electronic records. Data are collected retrospectively from 1 January 2017 to patient enrolment, and prospectively from patient enrolment until the end of December 2026. FINDINGS TO DATE: To date, the mean age is 68.3 (SD 12.2) years and 35.2% are female. The most common cause of kidney failure is diabetic nephropathy (37.4%). In January 2020, the facilities' median weekly doses of erythropoietin stimulating agent (ESA) and of intravenous vitamin D ranged from 1846 to 9692 IU (epoetin alfa equivalent) and 0.78 to 2.25 µg (calcitriol equivalent), respectively. The facilities' percentages of patients to whom calcimimetics are prescribed varied from 19% to 79%. During the retrospective period (averaging 1.85 years per participant), the incidence rates of any hospitalisation and of hospitalisation due to cardiovascular disease were 67.2 and 12.0 per 100 person-years, respectively. FUTURE PLANS: AQuAH-D data will be updated every 6 months and will be available for studies addressing a wide range of research questions, using the advantages of granular data and quality-of-life measurement of ageing patients on haemodialysis

Severity and Progression Rate of Cerebellar Ataxia in 16q-linked Autosomal Dominant Cerebellar Ataxia (16q-ADCA) in the Endemic Nagano Area of Japan

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.ArticleCEREBELLUM. 8(1):46-51 (2009)journal articl

ATM suppresses c-Myc overexpression in the mammary epithelium in response to estrogen

ATM遺伝子変異による乳癌発症機構を解明 --HBOC症候群の乳腺特異的発癌機構の解明に貢献--. 京都大学プレスリリース. 2023-02-09.ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis

Association of glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS): a cross-sectional study

Background While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). Methods This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of >= 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. Results Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (beta coefficient = - 2.54 [95% confidence interval - 4.48 to - 0.60], P = 0.01). Conclusions Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells

Analysis of the Burden of Bowel Preparation for Colonoscopy : A Qualitative Study Using Semi-structured Interviews

The burden of bowel preparation with laxatives and dietary restrictions is one of the reasons for the low acceptance rate of colonoscopies. This study aimed to extract concepts related to the burden of bowel preparation. Semi-structured interviews were conducted with 25 adults (13 men, median age 61 years [range 30-83 years]) who underwent a colonoscopy in an outpatient setting from June to August 2022. The interview contents were analyzed and classified into six categories of physical, psychological, and social burdens due to dietary restrictions and laxatives, respectively. The findings can be used to construct a scale that can comprehensively assess the burden of bowel preparation and improve strategies for this.大腸内視鏡検査の受検割合が低いことの原因の一つとして，食事制限と下剤で腸管内容物を排出させる処置（以下，大腸前処置)の負担が大きいことが挙げられる。本研究では，大腸前処置の負担感に関する概念を抽出することを目的とした。2022年6月～8月，外来で大腸検査を受検した成人25人（男性13人，年齢中央値61[範囲 30-83]歳)に対して，半構造化面接を行った。発言を分析し，食事制限と下剤のそれぞれによる身体的負担，心理的負担，社会的負担の6つのカテゴリに分類した。今回得られた知見は，大腸前処置の負担感を網羅的に評価可能な尺度の開発や，負担の軽い大腸前処置の確立につながることが期待される